The relative risk of developing a mental illness or neurological disorder varies considerably by gender. Males exhibit far higher rates of autism and autism spectrum disorder (ASD), Tourette's Syndrome, stuttering, dyslexia, and early onset of schizophrenia, all of which have a childhood onset. In contrast, females suffer much higher incidences of major depressive disorders, general anxiety disorder, anorexia, bulimia, and late onset of schizophrenia, all of which have adult onsets. The biological basis for these gender biases is entirely unknown. By exploring how the brain develops differently in males and females, using a mammalian animal model, we can gain insight into the potential sources of the sex differences in disease and identify potential therapeutic and preventive targets. Moreover, the gene FOXP2 is known to be expressed in several areas of the brain involved in vocal communication in animals and language in humans. There is strong support for FOXP2 playing a role in ASD can be found in its regulation of downstream signaling pathways. The mechanism that explains the basis for the gender difference in human language is also unknown, although, sex hormones, principally androgens, are known to play a central role in the development of vocalizations in a wide variety of animal species including primates. It has also been hypothesized that exposure to increased levels of androgens, during prenatal development, underpin the etiology of ASD, although to date, no relationship between any autism associated gene, language, or sex hormones has been established. The first goal of this proposal is to investigate how sex differences in Foxp2 expression influence the development of sex specific neural circuitry and how this circuitry is accountable for sex specific behaviors (e.g., vocal communication and social interactions). Experiments 1.1 and 1.2 are designed to fill the first gap in our knowledge, by exploring how suppression of Foxp2 during the neonatal developmental period impacts both vocalization and social behavior differently in males versus females. As discussed above, previous work investigating ASD and FOXP2, has not taken the perspective of the potential impact sex differences and hormones have on transcriptional signaling pathways regulated by FOXP2. Thus, A second goal of this proposal is to determine how sex hormones mediate Foxp2's regulation of gene expression. Experiments 2.1 and 2.2 are designed to address this question by assessing what are the effects sex hormones have on Foxp2 transcriptional signaling pathways. From previous research, it is known that Foxp2 influences the development of brain regions responsible for higher cognitive functioning. However, to date it is not known to what extent this development is similar or different with regards to male and female brain development. The third goal of this proposal is to ascertain the extent to which the interaction of sex hormones and Foxp2 alters sex specific neuronal development. Experiments 3.1 and 3.2 are designed to address this question by quantifying the impact sex hormones have on Foxp2 protein levels both in the presence and absence of lentiviral knockdown targeting Foxp2. For the R00 phase, I will write up the research collected from Aims 1.2 and Aims 2.1 and 2.1. I will then begin setting up my lab. Concurrent with opening the lab, I will begin work on Aim 3.

Public Health Relevance

The risk of developing a mental illness or neurological disorder varies considerably by gender. Thus, the current proposal focuses on how the brain develops differently in males and females. By exploring sex differences in brain development, it will be possible to gain insight into the potential sources of the sex differences in disease along with identifying potential therapeutic and preventative treatments.